Cyano-dicarboxylate

ABSTRACT

A phenylethyl substituted dimer of ethylene and maleic anhydride, named 7-phenyloctane-(1,2),(5,6)-dianhydride, is chemically synthesized by 
     (a) alkylating alkyl 2,4-dihalobutyrate with alkyl 2-cyano-3-phenylbutyrate, 
     (b) alkylating the resulting halide condensation product with a carboxylate selected from the group consisting of trialkyl ethane-1,1,2-tricarboxylate and dimethyl cyanoethane-1,2-dicarboxylate, 
     (c) acid hydrolyzing the resulting tetra or pentaester accompanied by decarboxylating, and 
     (d) dehydrating the resulting tetra-acid to yield the desired phenylethyl substituted dimer of ethylene and maleic anhydride, 
     wherein the alkyls in the butyrate and carboxylate ester groups each contain from one to about four carbon atoms and halo is selected from the group consisting of bromo, chloro and iodo.

This is a division of application Ser. No. 413,009, filed Apr. 30, 1982now U.S. Pat. No. 4,442,298.

BACKGROUND OF THE INVENTION

This invention relates to a phenylethyl substituted dimer of ethyleneand maleic anhydride and to a method for its complete chemical synthesiswithout polymerization. This dimer is appropriately named7-phenyloctane-(1,2),(5,6)-dianhydride.

It is well-known that various polyanionic compounds such as polyacrylicacid, pyran copolymer (divinylether/maleic anhydride) andethylene/maleic anhydride copolymer (EMA) have antitumor, antiviral andother pharmacological and biological properties. For example, polyanionshaving the following structural units have been found active againstboth the solid (intravascular) and ascitic (intraperitoneal) forms ofthe Walker carcinoma 256 of the rat as determined by the National CancerInstitute: ##STR1## See, for example, Hodnett and Tien Hai Tai, J. Med.Chem. 17 (12), 1335-1337 (1974). The ethylene and succinyl moieties inthe above polymeric structure are linked together by the polymerizationof ethylene and maleic anhydride.

More recently, it has been shown that certain ammoniated derivatives ofsuch ethylene/maleic anhydride polymers having relatively low molecularweight have enhanced antitumor and immunological activity. See U.S. Pat.Nos. 4,255,537 and 4,309,413. The average molecular weight of theseimproved polymers ranges from about 300 to about 1500. The smallestcomponent of these polymeric substances having a molecular weight ofabout 300 is essentially a dimer of ethylene and maleic anhydride.

The previously disclosed method of making the foregoing ethylene/maleicanhydride polymeric compounds of low molecular weight comprises thepolymerization of ethylene and maleic anhydride in the presence ofalkylated aromatic hydrocarbon having at least one α-hydrogen. Ethylbenzene is especially preferred. The use of ethyl benzene in thereaction medium results in the introduction of a phenylethyl end groupin the polymeric structure. Such end group constitutes a relatively highpercentage of the total structure for a polymer of relatively lowmolecular weight of about 300. The structure of these relatively lowmolecular weight polymers of ethylene and maleic anhydride having thephenylethyl end group can be represented as follows: ##STR2## See FIG. 1in Fields et al, J. Med. Chem. 25(9), 1060-1064 (1982), for a report ofthe above structure. When n in the above formula is equal to one, thepolymer would be a phenylethyl substituted dimer having a succinylanhydride terminal group and a molecular weight of 330.

The EMA type copolymers, including dimers, and their ammoniatedderivatives, are also known to be suitable for variousnon-pharmaceutical uses. Illustrative of such uses is the silver halidedispersion disclosed in U.S. Pat. No. 2,957,767. Othernon-pharmaceutical uses of low molecular weight EMA polymers prepared inethyl benzene solvent are described, for example, in U.S. Pat. No.2,913,437.

DESCRIPTION OF THE INVENTION

In accordance with the present invention, a phenylethyl substituteddimer of ethylene and maleic anhydride is prepared completely bychemical synthesis without polymerization.

In general, the method of the present invention comprises:

(a) alkylating alkyl 2,4-dihalobutyrate with alkyl2-cyano-3-phenylbutyrate,

(b) alkylating the resulting halide condensation product with acarboxylate selected from the group consisting of trialkyethane-1,1,2-tricarboxylate and dimethyl cyanoethane-1,2-dicarboxylate,

(c) acid hydrolyzing the resulting tetra or pentaester accompanied bydecarboxylating, and

(d) dehydrating the resulting tetra-acid to yield the desiredphenylethyl substituted dimer of ethylene and maleic anhydride,

wherein the alkyls in the butyrate and carboxylate ester groups eachcontain from one to about four carbon atoms and halo is selected fromthe group consisting of bromo, chloro and iodo.

The product made by the aforesaid method is conveniently describedherein as a phenylethyl substituted dimer of ethylene and maleicanhydride in view of conventional polymer nomenclature used heretoforeto describe substances of this type. This product also can beappropriately named 7-phenyloctane-(1,2),(5,6)-dianhydride based on itschemical structure.

In the method of the present invention, the stated alkyls in thebutyrate and carboxylate ester groups are preferably methyl and thestated halo substituents preferably are bromo.

The aforesaid stepwise production of the desired dimer can beillustrated by the following reaction equations in which the preferredmethyl ester groups and bromo substituents are employed in the reactantsand in which the carboxylate reactant is trimethylethane-1,1,2-tricarboxylate. It will be appreciated that, alternatively,the alkyls in the butyrate and carboxylate ester groups can be, forexample, ethyl, propyl or butyl, the halo substituents can be chloro oriodo, and the carboxylate reactant can be dialkylcyanoethane-1,2-dicarboxylate with substantially similar results as inthe preferred reaction sequence. ##STR3##

The initial reactants for step (a) in the preferred reaction sequencecan be prepared by conventional procedures. Thus, the starting methyl2-cyano-3-phenylbutyrate can be prepared by a Knoevenagel typecondensation of acetophenone and cyanoacetate followed by hydrogenationof the resulting unsaturated Knoevenagel adduct. The Knoevenagel typecondensation reaction of ketone with active methylene compounds wasfirst reported by Knoevenagel, Ber. 31, 2596 (1898).

The starting methyl 2,4-dibromobutyrate can be prepared by brominationof butyrolactone with phosphorus tribromide and bromine at 100°-120° C.followed by acid hydrolysis, e.g. with hydrochloric acid, in methanoland removal of the hydrogen halides and phosphate esters. Preparation ofmethyl 2,4-dibromobutyrate by this general reaction is known fromWladislaw, J. Org. Chem. 26, 711-713 (1961). Halogenation ofγ-butyrolactone to yield α,γ-dibromobutyric acid or α, γ-dichlorobutyricacid was earlier described by Livak et al., J. Amer. Chem. Soc. 67,2218-20 (1945) and in U.S. Pat. Nos. 2,530,348 and 2,557,779. However,in order to prevent elimination of hydrogen halide which would lead tothe formation of α-halo-γ-butyrolactone, the crude reaction product isconverted immediately into the corresponding ester.

The trimethyl ethane-1,1,2-tricarboxylate reactant which can be used instep (b) also is a known compound which was first described by C. A.Bischoff, Ber. 29 (1), 966-967 (1896). It can be prepared by reaction ofmethyl chloroacetate and dimethyl malonate in the presence of sodiummethoxide in methanol solvent.

The dimethyl cyanoethane-1,2-dicarboxylate reactant, which similarly canbe used in step (b), can be prepared by the reaction of methylcyanoacetate and methyl chloroacetate in the presence of potassiumcarbonate in dimethylformamide solvent by procedures analogous to themethod for alkylation of methyl 2-cyanopropionate described by D. A.White, Synthetic Comm. 7(8), 559-568 (1977).

The alkylation reactions in steps (a) and (b) also are each preferablycarried out in the presence of potassium carbonate in organic solventmedium such as, e.g., dimethylformamide (DMF) or dimethylsulfoxide(DMSO) solvent, in a manner analogous to the above cited method foralkylation of methyl 2-cyanopropionate.

The acid hydrolysis and decarboxylation in step (c) is convenientlycarried out with acid such as hydrochloric acid, preferably in about a1:1 solvent mixture of water and acetic acid at refluxing temperatureconditions.

The final step (d) of the synthesis which comprises dehydration of thetetra-acid is preferably carried out by reaction with acetyl chloride inboiling acetic anhydride. The desired dimer is thus obtained as acolored glassy solid. Overall yields using the aforesaid preferredprocess, including the Knoevenagel condensation reaction as an initialstarting point, have been in the range of 10-17% based on acetophenone.

The final phenylethyl substituted dimer of ethylene and maleic anhydrideis a useful intermediate which can be reacted with ammonia to produceammoniated derivatives of the type described in the aforesaid U.S. Pat.Nos. 4,255,537 and 4,309,413 and Fields et al., J. Med. Chem. 25(9),1060-1064 (1982). The dimer product is also suitable for variousnon-pharmaceutical uses such as described in U.S. Pat. Nos. 2,957,767and 2,913,437.

In the aforesaid stepwise process, it will be appreciated that thealkylation reactions can be conducted in the presence of basic reagentsother than potassium carbonate. Thus, sodium hydride and sodiummethoxide can be used in the alkylation reactions. So also, other acidmedia such as, for example, sulfuric acid can be used for the hydrolysisstep. The dehydration step alternatively can be carried out by refluxingin reagents such as p-toluenesulfonic acid in toluene or benzene solventand collecting the water in a Dean Stark trap.

The following detailed examples will further illustrate the inventionalthough it will be understood that the invention is not limited tothese specific examples.

In steps (a) and (b) of the method of the present invention asillustrated in the preferred reaction sequence, above, and in Examples3, 4 and 7 below, the following novel intermediate carboxylate compoundsare prepared:

Dimethyl 2-phenyl-3-cyano-6-bromohexane-3,4-dicarboxylate;

Pentamethyl 6-cyano-7-phenyloctane-1,2,2,5,6-pentacarboxylate; and

Tetramethyl 2,6-dicyano-7-phenyloctane-1,2,5,6-tetracarboxylate.

EXAMPLE 1 Methyl 2-cyano-3-phenylbutyrate

A mixture of methyl cyanoacetate (198 g, 2.0 moles), acetophenone (240g, 2.0 moles), ammonium acetate (30.8 g, 0.4 moles) and acetic acid (96g, 1.60 moles) in toluene was refluxed with a Dean and Stark trap untilwater separation ceased (about 4 hours). The resulting Knoevenageladduct was cooled and stirred under hydrogen (60 psig) with 5% palladiumon carbon (8 g) for 2 days. The solution was then depressurized,degassed, filtered and evaporated. The liquid residue was distilled andthe fraction with bp 110°-140° C. (about 0.03 mm) collected as mixedstereoisomers of methyl 2-cyano-3-phenylbutyrate as identified by thenmr spectrum.

EXAMPLE 2 Methyl 2,4-dibromobutyrate

A 3 liter round bottom flask equipped with a thermometer, subsurfaceadditional funnel, condenser vented to a scrubber and mechanical stirrerwas charged with butyrolactone (600 g; 6.98 moles) and phosphorustribromide (12 ml). Subsurface addition of bromine was initiated. Heatwas evolved and the rate was maintained at that necessary to keep thereaction mixture at about 110° C. After 71/2 hours, 1166 g (7.29 moles)of bromine had been added and the color of bromine persisted in thereaction mixture. Over the course of a further two days, repeatedadditions of phosphorus tribromide, which accelerated the rate ofbromine consumption and of bromine, were made at 100°-120°. Accordingly,1636 g (10.2 moles, 1.46 moles/mole butyrolactone) phosphorus tribromidewere added during the reaction period.

The cooled (<5°) reaction mixture was treated with methanol (2.5liters), while cooling in an ice-bath. The mixture was saturated withhydrogen chloride and allowed to stand at room temperature overnight.The solution was stripped of hydrogen halides and methanol leaving a twophase residue. The larger lower phase was separated and distilled (theupper layer appeared to be mainly phosphorus esters and was discarded).Two fractions were collected having bp 69°-72° (0.7-0.8 mm) (951 g) andbp 72°-9° (1.0 to 1.1 mm) (434 g). These fractions were washed with 3%aqueous sodium bicarbonate to remove phosphate esters and dried on arotary evaporator, to give 944 g and 426 g of methyl 2,4-dibromobutyrateproduct of 97% and 92% purity, respectively.

EXAMPLE 3 Dimethyl 2-phenyl-3-cyano-6-bromohexane-3,4-dicarboxylate

A mixture of methyl 2-cyano-3-phenylbutyrate (78 g, 0.37 mole), methyl2,4-dibromobutyrate (122 g, 0.47 mole), potassium carbonate (65 g, 0.47mole) and DMSO (50 ml) was stirred on a ball mill apparatus. Thereaction was completed in four hours. Ice water was added and themixture was neutralized by adding cold hydrochloric acid. The aqueoussolution was extracted several times with ether. The combined organicsolution was washed sequentially with cold aqueous sodium bicarbonateand brine, then dried over magnesium sulfate. After removal of thesolvent, the residue was purified by Kugelrohr distillation (100° C., 30microns) to remove low boiling materials. The remaining oily residue(118 g., 84%) was found to be mainly the title bromide condensationproduct (ν<95% GC purity). MS m/e (% relative intensity) 383(M⁺., 3) 381(3), 202 (33), 182 (7), 180 (7), 105 (100).

EXAMPLE 4 Pentamethyl 6-cyano-7-phenyloctane-1,2,2,5,6-pentacarboxylate

A mixture of the bromide condensation product of Example 3 (118 g, 0.3mole), trimethyl ethane-1,1,2-tricarboxylate (84 g, 0.41 mole),potassium carbonate (62 g, 0.45 mole) and DMSO (50 ml) was ball-milledfor about four days. GLPC indicated that the bromide reactant had beentotally consumed. Workup similar to that described above in Example 3gave a colored oil. The low-boiling impurities were removed viaKugelrohr (110° C., 20 microns) to give 120 g of the title pentaester.

MS M/e (% relative intensity): 501 (M⁺.,1), 474 (3), 304 (12), 204 (9),202 (10), 105 (100).

EXAMPLE 5 7-Phenyloctane-1,2,5,6-tetracarboxylic acid

A mixture of the pentaester product of Example 4 (120 g, 0.24 mole),concentrated hydrochloric acid (200 ml), water (200 ml) and acetic acid(200 ml) was refluxed for four days. The cloudy solution turned clearafter about 48 hours. Removal of solvents in vacuo gave a glass-likematerial which was then dissolved in acetone and was stirred overnight.The salt (ammonium chloride) was removed by filtration and the remainingsolution was condensed to afford 80 g of the glassy title tetra-acidproduct which was used in the sequential reaction of Example 6 withoutfurther purification. MS m/e (% relative intensity) 349 (CI, M⁺.+1 --H₂O),330 (M⁺. --2H₂ O,1), 303 (2), 284 (5), 105 (100).

EXAMPLE 6 7-Phenyloctane-(1,2),(5,6)-dianhydride

The crude tetra-acid product of Example 5 (˜70 g), acetyl chloride (60ml) and acetic anhydride (150 ml) were stirred and refluxed for 24hours. The solution was then concentrated to give a dark oily residue.This material was percolated in methylene chloride through acharcoal/silica gel column. The collected mixture was stripped ofsolvent and the low-boiling impurity was removed via Kugelrohr (120° C.,100 microns) to afford 61 g of thick oil which solidified upon standingat room temperature. This crude glassy solid of the title dianhydrideproduct displayed the following properties:

IR (CDCl₃). 2950, 1850, 1780, 1600 cm⁻² ; ¹ H NMR (CDCl₃) δppm 7.3 (S,phenyl-H), 1.2-4.0 (broad); MS m/e (% relative intensity) 331 (CI,M⁺.+1) 330 (M⁺, 3), 302 (6), 284 (16), 145 (25), 105 (100). C-13 NMR(CHCl₃) δppm for downfield absorptions: 173, 172, 171, 169 (anhydridecarbonyl), 140, 129, 128, 127 (aromatic carbons).

EXAMPLE 7 Tetramethyl2,6-dicyano-7-phenyloctane-1,2,5,6-tetracarboxylate

In a manner similar to the procedure of Example 4, dimethylcyanoethane-1,2-dicarboxylate was condensed with the bromide product ofExample 3 to give the title tetraester. MS M/e (% relative intensity):473 (CI, M⁺ +1), 441 (2), 239 (12), 202 (13), 105 (100).

The tetraester prepared in Example 7 can be used in place of anequivalent amount of the pentaester of Example 5 followed bysubstantially similar acid hydrolysis and decarboxylation to produce thetetracarboxylic acid of Example 5.

Ethyl 2-cyano-3-phenylbutyrate and ethyl 2,4-dichlorbutyrate can be usedin place of methyl 2-cyano-3-phenylbutyrate and methyl2,4-dibromobutyrate, respectively, in the alkylation reaction of Example3 to produce the corresponding diethyl2-phenyl-3-cyano-6-chlorohexane-3,4-dicarboxylate. The latter productcan then be reacted with the tricarboxylate of Example 4 and thedicarboxylate of Example 7 to give the corresponding pentaester andtetraester products.

In the foregoing Examples,

IR=Infrared Spectra,

NMR=Nuclear Magnetic Resonance Spectra, and

MS=Mass Spectra.

Various other examples will be apparent to the person skilled in the artafter reading the present disclosure without departing from the spiritand scope of the invention and it is intended that all such furtherexamples be included within the scope of the invention. What is claimedis:

1. Dimethyl 2-phenyl-3-cyano-6-bromohexane-3,4-dicarboxylate. 